The present invention relates to novel methods of using known pharmacological agents. The invention further relates to novel compositions employing these known pharmacological agents for the treatment of various conditions or diseases in animals. Particularly, the present invention relates to the use of these known pharmacological agents in the treatment of pathological mineral resorptive states in animals.
The mineral resorptive states whose treatment comprises the subject matter of the present invention are those states arising from physiological processes, particularly frankly pathological processes, in which loss of skeletal or dental structure transpires.
The mineral resorptive states characterized by the loss of dental structure include, for example, surface and/or inflammatory resorption of the dental root structure and dental ankylosis with replacement resorption. The dental demineralization resultant from these states is well known and they are readily diagnosed by an attending dentist or veterinarian.
The mineral resorptive states directly involving loss of skeletal structure include a wide variety of diseases and conditions. Further, certain mineral resorptive states are a recognized untoward consequence of numerous other diseases and conditions.
One principal class of mineral resorptive states are the various forms or types of osteoporosis. Osteoporosis refers to the abnormal rarefaction of bone, due to the failure of osteoblast to lay down bone matrix, excessive osteoclastic activity, or other disturbances of the osteoblastic-osteoclastic equilibrium. Rarefaction of bone refers to the condition of its becoming or being less dense, that is, being reduced in density, but not in volume. Osteoblasts are the cells which carry out the function of producing bone, and they function in the healthy vertebrate together with osteoclasts, cells whose function it is to absorb and remove bone.
Osteoporosis is a condition common in adults and typically results in a decrease in density of both the bone matrix (the substrate, collagen), and the bone mineral, Ca.sup.10 (PO.sup.4).sup.6 (OH).sup.2 or "hydroxyapatite". Osteoporosis typically results in numerous symptomatic manifestations, including back pain and deformation of the back bone. The bones of the afflicted animal also become brittle, which increases the likelihood and incidences of fractures. Various types of osteoporosis are known. See for example Dorland's Illustrated Medical Dictionary, 24th Edition, W. B. Saunders Company, London (1965). Among the types of osteoporosis are senile, attributed to the aging process; post-menopausal, attributable to the decreased ovarian production of estrogen following memopause; disuse, as a result of longterm immobilization; and steroidal, consequent to treatment with antiinflammatory steroids. Other notable disease states whose principal long-term pathology arises from a mineral resorptive state as a constituent thereof include Paget's disease, rheumatoid arthritis, and periodontal disease. For example, Paget's disease is characterized by initial bone decalcification and softening, followed by an abnormal calcium deposition. The abnormal recalcification leads to deformed bones and other untoward consequences. Somewhat similar in its ultimate effect is the pathological mineral resorptive state resulting from rheumatoid arthritis. In this disease condition, the inflammation of synovial tissues results in the demineralization of contiguous bone surfaces and abnormal mineralization of noncontiguous surfaces. The long-term effect of this disease process is typically immobilization of the affected joints due to the progressive malformation of bone structure. Finally, periodontal disease is also characterized by a pathological mineral resorptive state, which results in the resorption of the alveolar bone. The alveolar bone functions to support and anchor the teeth and its progressive resorption results in the loosening and subsequent loss of affected teeth.
Other disease conditions also induce mineral resorptive states in skeletal structures with resulting untoward effects on the affected animal. For example, hyperparathyroidism results in the excessive production of PTH (parathyroid hormone), an agent known to stimulate osteoclastic activity. Further, in many neoplastic diseases, the neoplasms, on contact with skeletal structures, induce pathological mineral resorptive states with resulting pathological consequences. For example, numerous types of mammary carcinoma cells are known to induce this pathological state.
Other neoplastic diseases also have the effect of inducing a pathological mineral resorptive state in skeletal structures. Such diseases include plasmacytomas, e.g., multiple myloma. For example, the latter disease is known to induce the production of excessive amounts of OAF (osteoclast activating factor), which results in excessive osteoclastic activity and consequent resorption of skeletal structures.
Finally, while the mineral resorptive state generally has attributed in the past to the excess activity of osteoclasts, to disturbances in the osteoblastic-osteoclastic equillibrium, and/or to infiltration of mineral tissues by neoplastic cells, the mineral resorptive state also may arise from activities of other cell types, solely, or in combination (for reference see Mindy, G.R., et al., "Direct Resorption of Bone by Human Monocytes", Science 196:1109-1111, 1977; Heersche, J. N. M., "The Mechanism of Osteoclastic Bone Resorption: A New Hypothesis", Proceedings, Mechanism of Localized Bone Loss, Eds., Horton, Tarpley, and Davis, Special Supplement to Calcified Tissue Abstracts, pp. 437-438, 1978; and Teitelbaum, S.L., et al., "Contact-Mediated Bone Resorption by Human Monocytes in Vitro", Proceedings, Mechanism of Localized Bone Loss, Eds., Horton, Tarpley, and Davis, Special Supplement to Calcified Tissue Abstracts, p. 443, 1978). Therefore, a mineral resorptive state may arise from a variety of cell-mediated events to result in the loss of skeletal or dental tissue.
Numerous antiosteoporotic agents, i.e., agents proposed for the treatment or prevention of osteoporosis, are known in the art. Such agents include anabolic steroids, various phosphorus-containing agents, vitamin D and related substances, estrogenic steroids, and calcitonin. Also, certain aromatic carboxylic acids have been described as useful antiosteoporotic agents. For a detailed review and discussion of such antiosteoporotic agents, see U.S. Pat. Nos. 4,125,621 or 4,101,688.
Numerous methods have been reported for assessing the effectiveness of antiosteoporotic agents. For example, one such report indicates that the effectiveness of any given antiosteoporotic agent may be determined by measuring the effect of such an agent on the production of cyclic AMP, utilizing isolated bone cells as the test medium according to the methods of Rodan, et al., J. B. C. 429:306 (1974) and Rodan, et al., Science 189:467 (1975). See U.S. Pat. No. 4,125,621 (Example 1) for a detailed description of this procedure.
An efficient means of assessing the inhibition of mineral resorptive states by a chemical agent is described by Horton, J. E., et al., "Inhibition of the In Vitro Bone Resorption by a Cartilage-Derived Anticollagenase Factor", Science 199:1342-1345 (Mar. 24, 1978). The method of Horton, et al. determines the ability of a chemical agent to block OAF, prostaglandin, and parathyroid hormone-stimulated (PTH-stimulated) .sup.45 Ca release from fetal rat bone in vitro. The relationship between the activity of osteoclasts in bone resorption and the acceleration of bone resorptive states induced by PTH-stimulation, both in vivo and in vitro is known. See Rasmussen, H., et al., "The Physiologic and Cellular Basis of Metabolic Bone Disease", Williams & Williams, Baltimore, 1974, pages 144-154.
The technique of Horton for measuring the inhibition of mineral resorptive states employs bone culture techniques described by Raisz, L. G., et al., Endocrinology 85:446 (1969). Paired shafts of the radius and ulna from 19 day old rat fetuses are radioactively labelled by injection of the mother with .sup.45 Ca on the day prior to culturing. The shafts are then cultured in the described medium containing (optionally) the chemical agent to be tested and/or a bone resorption stimulating agent such as PTH.
Mineral resorption of the skeletal structure is stimulated by addition of PTH/ml, typically 2.5 IU (International Units) every 48 hours. Cultures are maintained for 120-144 hours and the medium changed every 48 hours. The percentage of .sup.45 Ca released from bone into the culture medium is then used as a measure of bone resorption. The degree of mineral resorption is determined by liquid scintillation spectrometry from the counts per minute of .sup.45 Ca radioactivity present in the culture medium.
The known compounds employed in the novel methods and compositions disclosed herein are anti-allergenic agents, specifically including disodiumchromoglycate (DSCG) and DSCG anti-allergenic biologues. DSCG anti-allergenic biologues include anti-allergenic bis chromones related to DSCG as are described in U.S. Pat. No. 3,419,578. Further related anti-allergenic bis chromones are those described in U.S. Pat. Nos. 3,519,652 and 3,673,218. Moreover, DSCG anti-allergenic biologues, including anti-allergenic uses therefor, are described in U.S. Pat. No. 4,046,910, issued Sept. 6, 1977. The description of DSCG and related anti-allergenic bis chromones and their anti-allergenic compositions are incorporated here by reference from U.S. Pat. Nos. 3,419,578 and 4,046,910.
Another class of DSCG anti-allergenic biologues are the anti-allergenic benzopyrans, particularly the compounds described in U.S. Pat. Nos. 4,159,273, 3,786,071, 3,952,104, and 4,055,654. Notable among these compounds is proxicromil (FPL 57,787), 6,7,8,9-tetrahydro-5'-hydroxy-4-oxo-10-propyl-4H-naphtho[2,3-6]pyran-2-car boxylic acid, described in Example 8 of U.S. Pat. No. 4,159,273. The description and anti-allergenic compositions of these anti-allergenic benzopyrans is incorporated here by reference from U.S. Pat. Nos. 4,159,273, 3,786,071, 4,055,654, and 3,952,104.
Yet another class of DSCG anti-allergenic biologues are the anti-allergenic oxamic acids or derivatives thereof. These compounds, together with their anti-allergenic uses and compositions, are described in U.S. Pat. Nos. 3,993,679, 4,159,278, 4,095,028, 4,089,973, 4,011,337, 4,091,011, 3,972,911, 4,067,995, 3,980,660, 4,044,148, 3,982,006, 4,061,791, 4,017,538, 4,119,783, 4,113,880, 4,128,660, 4,150,140, 3,966,965, 3,963,660, 4,038,398, 3,987,192, 3,852,324, 3,836,541, and 3,836,164. The preparations of such compounds and their anti-allergenic compositions are incorporated by reference here from the aforementioned United States patents. One important anti-allergenic oxamate is iodoxamide, N,N'-(2-chloro-5-cyano-m-phenylene)amino methane salt.